Obsessive-compulsive disorder is a prevalent, chronic, and disabling disorder. Functional brain imaging studies suggest that OCD results from a malfunctioning brain circuit that includes the orbitofrontal cortex (OFC), the caudate nucleus, and the thalamus. Because the only medications known to reduce OCD symptoms are serotonin reuptake inhibitors (SRIs), it has been hypothesized that OCD is caused by an abnormality in the brain serotonin (5-HT) system. However, it remains unclear whether SRIs reduce OCD symptoms by correcting 5-HT dysfunction or by enhancing 5-HT modulation of brain circuits whose underlying dysfunction is unrelated to 5-HT. The 5-HT hypothesis of OCD remains largely untested, in part because it has been historically difficult to examine directly the 5-HT system in the living human brain. Advances in neuroreceptor imaging techniques now permit visualization of brain neurochemistry in humans using positron emission tomography (PET) and specific radioligands. Using this technology, Dr. Blair Simpson, the Principal Investigator, has worked with Dr. Marc Laruelle, a Co-investigator, to image different aspects of the brain 5-HT system in OCD subjects. Preliminary data suggest that OCD is associated with decreased availability of one type of receptor, the 5-HT2A receptor, in the OFC;however, these exciting preliminary findings require confirmation in a larger sample. The specific aim of this RO1 application is to quantify the regional distribution of 5-HT2A receptors in 24 patients with OCD and 24 matched controls using PET and a specific radioligand for 5-HT2A receptors ([1 lC]MDL 100907). If this study confirms that OCD is associated with decreased 5-HT2A receptor availability in the OFC, these data would provide direct evidence for altered 5-HT transmission in OCD and point for the first time to a postsynaptic abnormality in the OFC. Data from this study will advance our understanding of the brain mechanisms of OCD and help build a neurobiological foundation for the development of better treatments for this disabling condition.